Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma
Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma
复制标题
DOI：
10.1182/blood-2013-03-487884
复制
发表时间：
2013-07-11
期刊：
影响因子：
20.3
通讯作者：
Morgan, Gareth J.
中科院分区：
文献类型：
--
作者：
Kaiser, Martin F.;Johnson, David C.;Morgan, Gareth J.
多发性骨髓瘤的预后是高度可变的，更好地了解影响疾病生物学的因素对于理解和预测个体患者的行为至关重要。在本研究中，我们分析了医学研究委员会骨髓瘤IX试验中治疗的患者的全基因组DNA甲基化和基因表达数据。我们使用这些数据来鉴定骨髓瘤中表观遗传抑制的肿瘤抑制基因与预后的相关性。我们确定了195个甲基化状态变化的基因，这些基因与预后显著相关。结合DNA甲基化和基因表达数据，鉴定出表观遗传调控的肿瘤调节基因GPX3、RBP1、SPARC和TGFBI。这些基因的高甲基化与总生存期明显缩短相关，与年龄、国际分期系统评分和不良细胞遗传学无关。已知这4个差异甲基化和表达基因介导重要的肿瘤抑制功能，包括对化疗的反应（TGFBI）、与微环境的相互作用（SPARC）、视黄酸信号（RBP1）和对氧化应激的反应（GPX3），这可以解释它们的差异甲基化对预后的影响。评估鉴定基因的DNA甲基化状态有助于骨髓瘤的分子特征，这是个体化治疗方法的先决条件。
Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach.